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83 Health Technology Assessment 2012; Vol. 16: No. 23DOI: 10.3310/hta16230

Appendix 4

Data extraction tables: studies of clinical effectiveness

Kantarjian et al.6,7

Study details

Study details Population Arms Outcomes

Author(s): Kantarjian et al.

Year: 2007;6 updated 20097

Title: Dasatinib or HDI for CP-CML after failure of first-line imatinib: a randomised Phase II trial

Study: Kantarjian et al. (2007),6 (2009)7

Secondary publications: See PenTAG AR,2 appendix 3, for list of secondary publications

Trial code: START-R

CP: Yes

AP: No

BC: No

Countries: Argentina, Australia, Belgium, Brazil, Canada, Estonia, Finland, France, Germany, Israel, Republic of Korea, Norway, Peru, the Philippines, Poland, Puerto Rico, Russian Federation, South Africa, Sweden, Taiwan, Thailand, UK, USA

No. of centres: 58

Notes: NCT00103844

Inclusion criteria

Patients with CP-CML with primary or acquired resistance to conventional doses of imatinib (400–600 mg), dastinib naive, at least 18 years of age, and have adequate hepatic and renal function. CP was defined by the presence of < 15% blasts, < 20% basophils and < 30% blasts plus promyelocytes in peripheral blood or bone marrow and a platelet count of at least 100,000 per cubic millimetre, with no extramedullary involvement. Primary resistance to imatinib was defined as a lack of complete haematological response after 3 months of imatinib treatment, a lack of any CyR after 6 months of treatment or a lack of a MCyR (Ph+ cells > 35%) after 12 months of treatment. Relapse after a haematological response or MCyR was considered as secondary or acquired resistance

Exclusion criteria

Patients who had received imatinib in the 7 days before the study were ineligible, as were patients who had received imatinb at doses in excess of 600 mg per day. Patients with known specific BCR–ABL mutations (with high resistance to imatinib) before study entry were exclued

Method of allocation

Randomised 2 : 1 to receive dasatinib or HDI; randomisation was stratified by study site and CyR on imatinib (any response vs no response)

Blinding

Open label

Therapy common to all participants

Not reported

Arm 1: Dasatinib

n: 101

Drug: Dasatinib

Starting daily dose (mg): 140

Dosage details

70 mg b.i.d., escalated to 180 mg for participants with inadequate response at 12 weeks or progression

Reduced to 100 or 80 mg for participants experiencing toxicity

Notes

Crossover to the alternative treatment was permitted after confirmed progression, lack of MCyR at the week 12 cytogenetic evaluation or intolerance

Arm 2: HDI

n: 49

Drug: Imatinib


Dosage details: 400 mg b.i.d.

Reduction to 600 mg was permitted for toxicity in participants who had not previously received 600 mg ofimatinib

Notes: Crossover to the alternative treatment was permitted after confirmed progression, lack of MCyR at the week 12 cytogenetic evaluation or intolerance

CyR

Evaluated through bone marrow aspirates every 12 weeks

CCyR (0% Ph+)

PCyR (1% and 35% Ph+)

MCyR (complete + partial)

Duration of MCyR

Haematological response

Weekly blood counts for the first 12 weeks of treatment and every 2 weeks thereafter

CHR (WBCs ≤ institutional ULN; platelets < 450 × 109/l; no blasts or promyelocytes in peripheral blood; < 5% myelocytes plus metamyelocytes in peripheral blood; < 20% basophils in peripheral blood; no extramedullary involvement (including no hepatomegaly or splenomegaly)

Molecular response

MMR (not defined in paper or in study referenced as providing definitions of response; usually defined as a reduction in BCR–ABL transcript levels of at least 3 log)

Survival

Time to treatment failure [time from randomisation to progression (see PFS) or end of treatment (lack of response, study drug intolerance, or off treatment for any reason); subjects still on treatment were censored as of their last day of dosing]

Progression-free survival (time from randomisation until disease progression (accelerated-phase disease, BC, loss of CHR or MCyR, or increasing WBC count), death, or discontinuation of treatment because of progression prior to crossover)

Participant disposition

Withdrawal owing to AEs

AEs: grades 1–4

Assessed continuously and graded according to the NCI-CTC 3.0. Specific focus was given to cases of myelosuppression and fluid retention

BC, blast crisis; CCyR, complete cytogenetic response; CP-CML, chronic-phase CML; HDI, high-dose imatinib; MCyR, major cytogenetic response; NCI-CTC, National Cancer Institute Common Toxicity Criteria; PCyR, partial cytogenetic response: ULN, upper limit of normal; WBC, white blood cell.

84 Appendix 4

Baseline characteristics

Dasatinib HDI

p-valuen k Mean n k Mean

Demographics

Age (median) 101 51 (range 24 to 85)

49 51 (range 24 to 80)

Sex (n male) 101 53 (52.5%) 49 22 (44.9%) 0.486a

Imatinib failure

Resistance: loss of MCyR 101 21 (20.8%) 49 14 (28.6%) 0.395a

Resistance: loss of CHR 101 24 (23.8%) 49 15 (30.6%) 0.485a

Resistance: increasing WBC count 101 4 (4.0%) 49 2 (4.1%) 0.683a

Resistance: no CHR after 3 months 101 3 (3.0%) 49 2 (4.1%) 0.897a

Resistance: no CyR after 6 months 101 39 (38.6%) 49 16 (32.7%) 0.596a

Resistance: no MCyR after 12 months

101 39 (38.6%) 49 24 (49.0%) 0.303a

Prior therapy

Best response to imatinib: CHR 101 93 (92.1%) 49 47 (95.9%) 0.593a

Best response to imatinib: CCyR 101 15 (14.9%) 49 4 (8.2%) 0.372a

Best response to imatinib: PCyR 101 13 (12.9%) 49 10 (20.4%) 0.337a

Time on imatinib: < 1 year 101 12 (11.9%) 49 5 (10.2%) 0.977a

Time on imatinib: 1–3 year 101 44 (43.6%) 49 29 (59.2%) 0.105a

Time on imatinib: > 3 years 101 45 (44.6%) 49 15 (30.6%) 0.145a

Highest imatinib dose: > 400 mg/day 101 65 (64.4%) 49 35 (71.4%) 0.498a

Prior hydroxycarbamideb 101 97 (96.0%) 49 46 (93.9%) 0.860a

Prior chemotherapy 101 39 (38.6%) 49 18 (36.7%) 0.966a

Prior interferon 101 74 (73.3%) 49 33 (67.3%) 0.576a

Prior transplantation 101 7 (6.9%) 49 2 (4.1%) 0.747a

Disease history

Duration of CML (months) (median) 101 64 (range 6 to 166)

49 52 (range 14 to 133)

CHR at study entry 101 51 (50.5%) 49 27 (55.1%) 0.722a

Baseline status

CHR at study entry 101 51 (50.5%) 49 27 (55.1%) 0.722a

Disease history

MCyR at study entry 101 6 (5.9%) 49 0 (0.0%) 0.283a

Baseline status

MCyR at study entry 101 6 (5.9%) 49 0 (0.0%) 0.283a

Imatinib failure

BCR–ABL mutation 101 41 (40.6%) 46c 11 (22.4%) 0.045a

Baseline status

BCR–ABL mutation 101 41 (40.6%) 49 11 (22.4%) 0.045a



Dasatinib HDI


Laboratory parameters

WBCs × 109/l (median) 100c 7.5 (range 2 to 153) 48c 7.4 (range 2 to 133)

WBCs: 20 × 109/l or more 101 11 (10.9%) 49 7 (14.3%) 0.740a

Platelets × 109/l (median) 101 261c (range 55 to 1903) 49 248 (range 80 to 2318)

CCyR, complete cytogenetic response; HDI, high-dose imatinib; MCyR, major cytogenetic response; PCyR, partial cytogenetic response: WBC, white blood cell.a Chi-squared test (Yates’s correction) (calculated by reviewer).b Hydroxycarbamide or anagrelide.c Data from Kantarjian et al.7 given here differs from those in earlier publications.

Results

Dasatinib HDI


kantarjian et al. (2007)6

At median follow-up, 15 months (range 1 to 21 months)a

CyR

CCyR 101 40 (39.6%) 49 8 (16.3%) 0.007b

PCyR 101 13 (12.9%) 49 8 (16.3%) 0.748b

MCyR 101 53 (52.5%) 49 16 (32.7%) 0.035b

Duration of MCyR: 0 months 53 1 16 1

Duration of MCyR: 12 months 7 0.98 0 0.425




CHR 101 94 (93.1%) 49 40 (81.6%) 0.065b

Molecular response

MMR 101 16 (15.8%) 49 2c (4.1%) 0.070b

Study medication

Duration of study therapy (months) (median)

101 13.7 (range 0.2 to 19.3) 49 3.1 (range 0.2 to 15.6)

Average daily dose (mg/day) (median) 101 103 (range 38 to 175) 49 796 (range 358 to 800)

Survival

Time to treatment failure: 0 months 101 1 49 1

Time to treatment failure: 12 months 66 0.74 9 0.205


Time to treatment failure: 18 months 4 0.715




PFS: 0 months 101 1 49 1

PFS: 12 months 66 0.925 9 0.73

PFS: 15 months 17 0.925 0 0.545

86 Appendix 4

Dasatinib HDI


PFS: 18 months 4 0.925

PFS: 3 months 95 0.99 36 0.87

PFS: 6 months 86 0.975 10 0.73

PFS: 9 months 79 0.94 10 0.73

Median time to treatment failure (months)

Not reached 3.5 (95% CI 3.3 to 3.8)

Participant disposition

Withdrawal owing to AEsd 101 16 (15.8%) 49 9 (18.4%)

AEs grades 1–4

Anorexia 101 13 (12.9%) 49 4 (8.2%) 0.748b

Asthenia 101 13 (12.9%) 49 2 (4.1%) 0.563b

Diarrhoea 101 35 (34.7%) 49 14 (28.6%) 0.008b

Dyspnoea 101 21 (20.8%) 49 2 (4.1%) 0.087b

Face oedema 101 4 (4.0%) 49 5 (10.2%) 0.003b

Fatigue 101 30 (29.7%) 49 11 (22.4%) 0.099b

Headache 101 25 (24.8%) 49 5 (10.2%) 0.701b

Muscle spasms 101 2 (2.0%) 49 6 (12.2%) < 0.001b

Nausea 101 24 (23.8%) 49 16 (32.7%) < 0.001b

Pain in extremity 101 7 (6.9%) 49 5 (10.2%) 0.030b

Peripheral oedema 101 10 (9.9%) 49 10 (20.4%) < 0.001b

Pleural effusion 101 17 (16.8%) 49 0 (0.0%) 0.009b

Pyrexia 101 14 (13.9%) 49 5 (10.2%) 0.431b

Rash 101 17 (16.8%) 49 7 (14.3%) 0.147b

Superficial oedema 101 15 (14.9%) 49 21 (42.9%) < 0.001b

Vomiting 101 9 (8.9%) 49 12 (24.5%) < 0.001b

Weight increase 101 5 (5.0%) 49 5 (10.2%) 0.008b

Haematological AEs grades 3–4

Thrombocytopenia 101 57 (56.4%) 49 7 (14.3%)

Neutropenia 101 62 (61.4%) 49 19 (38.8%)

AEs grades 3–4

Anorexia 101 0 (0.0%) 49 0 (0.0%) 0.482b

Asthenia 101 0 (0.0%) 49 0 (0.0%) 0.482b

Diarrhoea 101 2 (2.0%) 49 1 (2.0%) 0.835b

Dyspnoea 101 4 (4.0%) 49 0 (0.0%) 0.533b

Face oedema 101 0 (0.0%) 49 0 (0.0%) 0.482b

Fatigue 101 2 (2.0%) 49 2 (4.1%) 0.171b

Headache 101 2 (2.0%) 49 1 (2.0%) 0.835b

Muscle spasms 101 0 (0.0%) 49 0 (0.0%) 0.482b

Nausea 101 0 (0.0%) 49 0 (0.0%) 0.482b

Pain in extremity 101 0 (0.0%) 49 1 (2.0%) 0.209b

Peripheral oedema 101 0 (0.0%) 49 0 (0.0%) 0.482b

Pleural effusion 101 4 (4.0%) 49 0 (0.0%) 0.533b

Pyrexia 101 0 (0.0%) 49 0 (0.0%) 0.482b

Rash 101 0 (0.0%) 49 0 (0.0%) 0.482b

Superficial oedema 101 0 (0.0%) 49 0 (0.0%) 0.482b

Vomiting 101 0 (0.0%) 49 0 (0.0%) 0.482b

Weight increase 101 0 (0.0%) 49 0 (0.0%) 0.482b



Dasatinib HDI


kantarjian et al. (2009)7

At 12 weeks

CyR

CCyR 101 22 22% 49 4 8% 0.041

MCyR 101 36 36% (26.4% to 45.8%) 49 14 29% (16.6% to 43.3%) 0.402

At median follow-up 26 months (range 6.9 to 32.7 months)a

Estimated proportion without treatment failure at 24 months

101 59% 49 18%

Estimated progression-free survival at 24 months

101 86% 49 65% 0.0012

Estimated progression 101 13 49 10

600 mg/day subgroup 63 11 34 8 0.0033

400 mg/day subgroup 36 2 14 2 0.0562

Primary resistance subgroup 53 4 24 2 0.2110

Acquired resistance subgroup 43 9 24 8 0.0069

Before crossovere

CyR

CCyR 101 44 44% 49 9 18% 0.0025

PCyR 101 10 10% 49 7 14%

MCyR (95% CI) 101 54 53% (43.3% to 63.5%) 49 16 33% (19.9% to 47.5%) 0.017

Previous imatinib 600 mg/day 63 32 51% 34 8 24%


% (95% CI) without loss of a MCyR at 18 months

54 90% (82% to 98%) 16 74% (49% to 100%)

MCyR in patients with a previous CyR on imatinib

All 62 34 55% 34 15 44%



MCyR in patients without a previous CyR on imatinib

All 39 20 51% 15 1 7%



CyR by imatinib resistancef

Primary resistance 53 24

MCyR 53 30 57% 24 7 29%

CCyR 53 22 42% 24 3 13%

Acquired resistance 43 24

MCyR 43 21 49% 24 8 33%

CCyR 43 19 44% 24 5 21%

With protocol-specified mutations 17 2

MCyR 17 7 41% 2 0 0%

CCyR 17 4 24% 2 0 0%

88 Appendix 4

Dasatinib HDI



CHR (95% CI) 101 94 93.1% (86.25% to 97.2%) 49 40 81.6% (68% to 91.2%) 0.0341

Without loss of CHR at 24 months,% (95% CI)

84% (76% to 93%) 73% (49% to 96%)

Timing not specified

CCyR in patients without a baseline CCyR

97 41 42% 49 9 18%

MCyR in patients without a baseline MCyR

95 49 52% 49 16 33%

MMR 101 29 29% 49 6 12% 0.028

MMR in patients who had a CCyR and a molecular response assessment

44 28 64% 9 5 56%

CHR in patients without CHR at baseline

50 43 86% 22 16 72%

Treatment

Median (range) treatment duration (months)

101 23 (0.16 to 29.4) 49 3 (0.16 to 26.3)

Median (range) dose (mg/day) 101 105 (42 to 177) 49 796 (358 to 800)

Dose interruptions 101 86 85% 49 17 35%

For haematological toxicity 101 62 61% 49 8 16%

For non-haematological toxicity 101 18 18% 49 4 8%

Dose reductions 101 71 70% 49 6 12%

For haematological toxicity 101 47 47% 49 2 4%

For non-haematological toxicity 101 14 14% 49 2 4%

Withdrawalsd

From initial therapy 101 50 50% 49 40 82%

Due to AEs 101 23 23% 49 10 20%

Due to haematological AEs 101 10 10% 49 4 8%

Due to non-haematological AEs 101 13 13% 49 6 12%

Among patients who achieved a MCyR

Due to loss of major haematological response

5% 6%

Due to intolerance 3% 4%

Due to other reasons 1% 4%

AEs grades 1–4g,h

Treatment related 101 94 93% 49 44 90%

Abdominal pain 101 15 15% 49 4 8%

Anorexia 101 17 17% 49 4 8%

Asthenia 101 15 15% 49 2 4%

Bleeding 101 18 18% 49 4 8%

Diarrhoea 101 37 37% 49 14 29%

Dyspnoea 101 23 23% 49 2 4%

Face oedema Not reported Not reported

Fatigue 101 33 33% 49 11 22%

Fluid retention 101 39 39% 49 21 43%

Headache 101 26 26% 49 5 10%



Dasatinib HDI


Infection 101 14 14% 49 3 6%

Muscle spasms Not reported Not reported

Musculoskeletal pain 101 21 21% 49 6 12%

Nausea 101 24 24% 49 16 33%

Pain in extremity Not reported Not reported

Peripheral oedema Not reported Not reported

Pleural effusion 101 25 25% 49 0 0%

Pyrexia 101 14 14% 49 5 10%

Rash 101 18 18% 49 10 20%

Superficial oedema 101 20 20% 49 21 43%

Upper respiratory tract infection or inflammation

101 11 11% 49 3 6%

Vomiting 101 10 10% 49 12 24%

Weight increase Not reported Not reported

AEs grades 3–4

Treatment related 101 62 61% 49 19 39%

Abdominal pain 101 0 0% 49 1 2%

Anorexia 101 0 0% 49 0 0%

Asthenia 101 0 0% 49 0 0%

Bleeding 101 1 1% 49 0 0%

Diarrhoea 101 3 3% 49 1 2%

Dyspnoea 101 5 5% 49 0 0%

Face oedema Not reported Not reported

Fatigue 101 3 3% 49 2 4%

Fluid retention 101 7 7% 49 0 0%

Headache 101 2 2% 49 1 2%

Infection 101 4 4% 49 0 0%

Muscle spasms Not reported Not reported

Musculoskeletal pain 101 1 1% 49 1 2%

Nausea 101 0 0% 49 0 0%

Pain in extremity Not reported Not reported

Peripheral oedema Not reported Not reported

Pleural effusion 101 5 5% 49 0 0%

Pyrexia 101 0 0% 49 0 0%

Rash 101 0 0% 49 0 0%

Superficial oedema 101 1 1% 49 0 0%

Upper respiratory tract infection or inflammation

101 1 1% 49 0 0%

Vomiting 101 0 0% 49 0 0%

Weight increase Not reported Not reported

Haematological AEs grades 3–4

Anaemia 101 20 20% 49 4 8%

Leucopenia 101 24 24% 49 8 16%

Neutropenia 101 64 63% 49 19 39%

Thrombocytopenia 101 58 57% 49 7 14%

Death 101 2 49 0

90 Appendix 4

CCyR, complete cytogenetic response; HDI, high-dose imatinib; MCyR, major cytogenetic response; PCyR, partial cytogenetic response; PFS, progression-free survival; SCT, stem cell transplantation.a Some follow-up times exceed the time to treatment crossover (see footnote ‘e’), but it is not reported whether these refer only to patients who

did not cross over or whether any data from crossovers are included. Note that only nine patients did not cross over to dasatinib.b Chi-square test (Yates’ correction) (calculated by reviewer).c Reported as 2/49 in text, but 4/49 in table (noted by SHTAC).d Before crossover.e Crossover details: only pre-crossover data have been extracted:

– 39 (80%) originally randomised to HDI: median time to crossover 13 weeks (range 1 to 68 weeks). – 20 (20%) initially randomised to dasatinib: median time to crossover 34 weeks (range 1 to 108 weeks).

f Excluding six patients for whom no reasons for previous imatinib resistance were available.g Patients may have had more than one AE.h AEs in ≥ 10% of patients.No grade 4 AEs seen in either group.A range of subgroup analyses are also available (according to the following: pretreatment CyR status; participants with prior chemotherapy; participants with prior SCT; participants with history of imatinib 600 mg/day; participants with no prior CHR with imatinib; participants with no prior CyR with imatinib; participants with BCR–ABL mutation). Significant inter-treatment differences in rate of MCyR observed in participants with history of Imatinib 600 mg/day and participants with no prior CyR with imatinib. Data are also presented for specific BCR–ABL point mutations. Full data not extracted here.Note that data have been extracted here as reported in the paper, for example rounded to whole number. However, outcomes summarised in the main text of the present report may have been calculated to one decimal place by reviewers.



Quality appraisal

1. Is a power calculation provided? NO

2. Is the sample size adequate? NOT CLEAR [stated that sample size was based on achieveing a maximum 20% (dasatinib) and 29% (imatinib) width of the 95% CI for the primary outcome: however, the non-standard percentage width suggests this may have been a post hoc observation, especially as not reported in the earlier publications]

3. Was ethical approval obtained? YES

4. Were the study eligibility criteria specified? YES

5. Were the eligibility criteria appropriate? YES

6. Were patients recruited prospectively? YES

7. Was assignment to the treatment groups really random? UNKNOWN

8. Were groups stratified? YES (by study site and CyR on imatinib)

9. Was the treatment allocation concealed? UNKNOWN

10. Are adequate baseline details presented? YES

11. Are the participants representative of the population in question? YES

12. Are groups similar at baseline? YES. Well balanced with one exception: approximately twice as many patients in the dasatinib treatment arm (45%) had a BCR–ABL mutation than in the HDI group (22%)

13. Are any differences in baseline adequately adjusted for in the analysis? YES (earlier publications)/NOT REPORTED (Kantarjian et al.7)

14. Are outcome assessors blind? NOT CLEAR

15. Was the care provider blinded? NO, open label

16. Are outcome measures relevant to research question? YES

17. Are data collection tools shown or known to be valid for the outcome of interest? YES

18. Is compliance with treatment adequate? UNCLEAR

19. Are withdrawals/dropouts adequately described? YES

20. Are all patients accounted for? YES

21. Is the number randomised reported? YES

22. Are protocol violations specified? NO

23. Are data analyses appropriate? NO (analyses were not planned in the original study and the analyses subsequently conducted were not adjusted for multiple comparisons)

24. Is analysis conducted on an ITT basis? YES (earlier publications)/NOT REPORTED (Kantarjian et al.7)

25. Are missing data appropriately accounted for? NOT REPORTED

26. Were any subgroup analyses justified? YES

27. Are the conclusions supported by the results? NO, open label; relatively small sample size; lack of power calculation; unplanned crossover; results from subgroup analyses were based on small sample size

28. Generalisability: Flaws in the study methodology impaired the internal validity of the study results

29. Inter-centre variability: Not taken into account

30. Conflict of interest declared? YES

31. General comments: Note that for outcomes reported ‘before crossover’ there is very wide variability in the time to crossover, which makes interpretation of the timing of the outcomes uncertain. The timing of some assessments seems to exceed the timing of crossover and it is unclear whether later assessments included crossover patients (only nine HDI patients did not cross over to dasatinib). Note that AEs are reported for all patients including crossovers, but it is not stated whether the events occurred before or after crossover or whether event frequencies differed before and after crossover

HDI, high-dose imatinib.

92 Appendix 4

Breccia et al.9

Study details

Study details Population Arms OUTCOMES

Study: Breccia et al. (2010)9

Design: Cohort single arm; judged to be prospective although unclear reporting

Chronic phase: Yes

AP: No

BC: No

Country: Italy

No. of centres: 2

Notes

Investigated the long-term efficacy of dose escalation in patients with CP-CML who demonstrated a poor response or relapse after standard imatinib therapy

Inclusion criteria

CML patients who demonstrated a poor response or relapse after standard imatinib therapy; no other inclusion information given other than the table of baseline characteristics (below)

Exclusion criteria

Not reported

Arm 1

n: 74

Drug: HDI

Starting daily dose (mg): 600 or 800

Dose details

Dose escalation to 600 or 800 mg/day if haematological failure, imatinib resistancea or suboptimal responseb

Concurrent treatment

None reported

CyR


Molecular response

Stated that CyR was assessed before dose escalation and thereafter at 3 and 6 months of therapy then every 6 months

Survival

Defined as the time from diagnosis to death or date of last follow-up

Progression-free survival

Defined from the time of the start of imatinib to progression to an advanced phase of disease

AEs

(Not explicitly specified as an outcome)

AP, accelerated phase; BC, blast crisis; CCyR, complete cytogenetic response; CP-CML, chronic-phase CML; CyR, cytogenetic response; HDI, high-dose imatinib; PCyR, partial cytogenetic response. a Haematological and cytogenetic resistance not defined separately; imatinib failure defined as lack of CHR at 3 months, and of CyR at 6

months, the attainment of less than PCyR at 12 months, of less than CCyR at 18 months; or the loss of CHR, CCyR; or acquisition of BCR–ABL mutations at any time.

b Suboptimal response defined as incomplete haematological response at 3 months, less than PCyR at 6 months, less than CCyR at 12 months and less than MMR at 18 months, or acquisition of cytogenetic abnormalities in Ph+ cells, mutations of BCR–ABL, or loss of MMR at any time.


Intervention

n k Median (range), percentage or score

Demographics

Age, years: median (range) 74 50 (19 to 85)

Sex (n male) 74 52 70.3%a

Disease status

WBC count (× 109/l) 74 4.5 (3.8 to 6.2)b

Platelet count (× 109/l) 74 220 (180 to 350)b

Haemoglobin concentration (g/dl) 74 13 (11.8 to 15)b

Sokal score

Low 74 41b

Intermediate 74 24b

High 74 9b

Treatment history

IFN-α (late CP-CML) 74 22 29.7%a

Standard-dose imatinib only (early chronic phase) 74 52 70.3%a



Intervention

n k Median (range), percentage or score

Cause of imatinib dose escalation

Primary resistancec 74 34 45.9%a

Haematological 74 10 13.5%a

Cytogenetic 74 24 32.4%a

Secondary resistancec 74 36 48.6%a

Haematological 74 3 4.1%a

Cytogenetic 74 33 44.5%a

Suboptimal responsec 74 4 5.4%a

Cytogenetic 3

Molecular 1

Median (range) time from diagnosis to therapy (months) 74 3 (1 to 13)

Median (range) duration of imatinib therapy (months) 74 36 (21 to 70)

Dose escalation

From 400 to 600 mg/day 74 54 73.0%c

From 400 to 800 mg/day 74 20 27.0%c

CCyR, complete cytogenetic response; CP-CML, chronic-phase chronic myeloid leukaemia; IFN-α, interferon alfa; PCyR, partial cytogenetic response; WBC, white blood cell.a Calculated by reviewer.b Parameter (e.g. mean, median) not stated.c Haematological and cytogenetic resistance not defined separately; imatinib failure defined as lack of CHR at 3 months, and of CyR at 6

months, the attainment of less than PCyR at 12 months, of less than CCyR at 18 months; or the loss of CHR, CCyR; or acquisition of BCR–ABL mutations at any time.

Results

Intervention

n k Median, percentage or p-value

At 36 months’ median follow-up

Maintained or achieved a CCyRa 74 27 36.4%b

Haematological failure patients 13 5 38%

Cytogenetic resistant patients 57 22 39%c

Difference between subgroups p = 0.345

Primary cytogenetic resistance subgroup 24 27%

Acquired cytogenetic resistance subgroup 33 50%


Achieved a MCyRa

Cytogenetic failure 57 41 72%

Haematological failure 13 6 46%


Achieved a CyRa

600-mg/day dose escalation subgroup 53d 40

800-mg/day dose escalation subgroup 20 10


94 Appendix 4

Intervention


Median time to a CyR (months) 3.5

Maintained or achieved a CHRe 74 68 91.8%

Achieved a complete molecular responsef 74 10

Cytogenetic failure 10 7

Escalated dose for suboptimal CyR 10 3

Estimated 2-year outcomes

PFS 87%

OS 85%

AEsg

Muscle cramps

600-mg/day imatinib subgroup 20%

800-mg/day subgroup 30%

Difference between subgroups NS (p ≥ 0.05)

Peripheral oedema



Difference between subgroups NS (p ≥ 0.05)

Haematological toxicity

Anaemia



Difference between subgroups Not reported

Neutropenia




CCyR, complete cytogenetic response; MCyR, major cytogenetic response; NS, not statistically significant; OS, overall survival; PCyR, partial cytogenetic response; PFS, progression-free survival; WBC, white blood cell.a Definitions of CyRs: CCyR: Ph+ metaphases = 0%; PCyR: Ph+ metaphases = 1–35%; MCyR: Ph+ metaphases = 0–35%; minor CyR: Ph+

metaphases = 36–65%; minimal CyR: Ph+ metaphases = 66–95%; no CyR: Ph+ metaphases > 95%b Reported by authors as 37%.c Calculated by reviewer as 39%; reported by authors as 42%.d Reported elsewhere that 54 patients escalated dose to 600 mg/day.e Authors refer both to CHR and ‘complete haematological remission’ using the same abbreviation (CHR). Complete haematological remission

is defined as a WBC count of < 10 × 109/l with no immature cells in the peripheral blood, a platelet count of < 450 × 109/l, and disappearance of all signs and symptoms related to leukaemia. Partial haematological response is defined as the persistence of peripheral immature cells or persistence with improvement of > 50% of splenomegaly and degree of thrombocytosis.

f Definitions of molecular responses: complete molecular response, a BCR–ABL/ABL ratio of < 0.001; MMR, a BCR–ABL/ABL ratio of < 0.1.g Grades of AEs not reported.



Quality appraisal

1. General

1.1. Is the hypothesis/aim/objective of the study clearly described? YES

1.2. Were the case series collected at more than one centre? YES

1.3. Was the main outcome independently assessed? NOT REPORTED

1.4. Are patient characteristics adequately described? YES (baseline characteristics reported)

1.5. How easy is it to assess generalisability of the results? LOW (Italian population, but inclusion and exclusion criteria not stated)

2. Assessment of selection bias

2.1. Are inclusion and exclusion criteria clearly reported? NO

2.2. Were data collected prospectively? NOT REPORTED

2.3. Were patients recruited consecutively? NOT REPORTED (a date range for recruitment is given)

3. Assessment of performance bias

3.1. Did all of the participants receive the same intervention? NO (subgroups received different dose escalations)

3.2. Is the use of any concurrent therapies adequately described? NO (not reported whether there were any concurrent therapies)

4. Assessment of attrition bias

4.1. Was an ITT analysis performed? UNCLEAR (not explicitly reported; dropouts not reported)

4.2. Were dropouts from the study adequately described? NO

96 Appendix 4

Koh et al.10

Study details


Study: Koh et al. (2010)10

Design: Prospective cohort single arm

CP: Yes (n = 64)

AP: Yes (n = 3)

BC: Yes (n = 4)

Country: Korea

No. of centres: 19

Notes

Phase IV study to evaluate the efficacy of escalated dose imatinib in patients with suboptimal response to standard-dose imatinib

Inclusion criteria

CML patients between 15 and 75 years of age with adequate organ function (not defined). Patients in CP with suboptimal response to 400 mg/day of imatinib; patients in AP or BC who failed to achieve CHR after 3 months on 400–600 mg/day of imatinib

Suboptimal response and treatment failure were defined according to European LeukemiaNET (reference cited)

Exclusion criteria

Patients who experienced more than grade 2 AEs to standard-dose imatinib

Arm 1

n: 71

Drug: HDI


Dose details

Dose escalation to 800 mg/day permitted in patients with AP or BC. Escalated doses were for a minimum of 12 months or until disease progression or intolerable toxicity. Patients with cytopenia and non-haematological toxicity of grade 3 or more received dose reduction from 800 to 600 mg/day then 400 mg/day; or from 400 to 300 mg/day. Patients experiencing more than grade 3 toxicity on 300 mg/day were withdrawn. An effort was made to increase dose if patients on reduced dose for 1 month did not experience more than grade 1 toxicity


None reported

CyR

Assessed every 6 months

Molecular response

Assessed every 3 months

Time to treatment failure

Defined according to LeukemiaNET (reference cited), based on cytogenetic evaluation; refers to the time from dose escalation to the time of treatment failure or drug discontinuation due to intolerable toxicity

AEs

(Not explicitly specified as an outcome)

AP, accelerated phase; BC, blast crisis; CP, chronic phase; CyR, cytogenetic response; HDI, high-dose imatinib.


Intervention

n k Median (range) or percentage

Demographics

Age, years: median (range) 71 49 (20 to 71)

Sex (n male) 71 50 70.4%

Disease status

CP 71 64 90.1%

AP 71 3 4.2%

BC 71 4 5.6%

CyRa

Partial 71 31 43.7

Less than partial 71 40 56.3

Median (range) duration (months) of standard-dose imatinib 14.6 (0.6 to 52.8)

Treatment outcome on standard-dose imatinib

Suboptimal response 71 19 26.8

Treatment failure 71 52 73.2

Dose escalation

To 600 mg/day 71 65 91.5

To 800 mg/day 71 6 8.5

AP, accelerated phase; BC, blast crisis; CCyR, complete cytogenetic response; CP, chronic phase; CyR, cytogenetic response; PCyR, partial cytogenetic response.a According to the cited European LeukemiaNET reference, the following definitions apply: CCyR, Ph+ = 0%; PCyR, Ph+ = 1–35%; less than

PCyR, Ph+ > 35%Authors stated in the discussion section that there were 9.7% mutations, but in the results section they reported that 3 out of 61 evaluable patients (4.9%) had mutations.



Results

Intervention


At 6 months’ follow-up

Evaluable for CyR 71 52 73.2%a

Unevaluable owing to early disease progression 71 4 5.6%a

Unevaluable owing to refusal or loss to follow-up 71 15 21.1%a

Achieved a CyRb

Complete 71 16 22.5%

Partial 71 14 19.7%

Less than partial 71 22 31.0%

Overall rate of achieving a CCyR for evaluable patients 52 16 30.8%

Frequency achieving a CCyR, by subgroups

A. Partial responders at baseline Not reportedc

B. Less than partial responders at baseline Not reportedc

Difference, subgroups A vs B p = 0.034

C. Suboptimal response on standard dose at baseline Not reported

D. Treatment failure on standard dose at baseline Not reported

Difference, subgroups C vs D p = 0.076

E. Early molecular respondersd Not reportede

F. Non-early molecular responders Not reportede

Difference, subgroups E vs F p = 0.010

Evaluable for molecular response 71 61 85.9%a


Unevaluable owing to loss to follow-up 71 6 8.5%a

Achieved a molecular response

Early molecular responsed 71 40 56.3%

AP patients achieving 3 2

BC patients achieving 4 0

Non-early molecular response 71 21 29.6%

At 12 months’ follow-up

Evaluable for CyR 71 43 60.6%a


Unevaluable owing to refusal or loss to follow-up 71 16 22.5%a

Achieved a CyRb

Complete 71 17 23.9%

Partial 71 11 15.5%

Less than partial 71 14 19.7%

Overall rate of achieving a CCyR for evaluable patients 43 17 40.5%

98 Appendix 4

Intervention


Frequency achieving a CCyR, by baseline subgroups

A. Partial responders at baseline Not reportedc

B. Less than partial responders at baseline Not reportedc

Difference, subgroups A vs B p = 0.012

C. Suboptimal response on standard dose at baseline Not reported

D. Treatment failure on standard dose at baseline Not reported


E. Early molecular respondersd Not reportede

F. Non-early molecular responders Not reportede

Difference, subgroups E vs F p < 0.001

Median time to treatment failure (months) 71 18

CP patients 27.0

AP patients 2.5

BC patients 4.0

Difference between CP and AP/BCf p < 0.001

Comparisons by subgroups:

A. Partial cytogenetic responders at baseline Not reached

B. Less than partial cytogenetic responders at baseline 12.0

Difference, subgroups A vs B p < 0.001

C. Suboptimal response on standard dose at baseline Not reached

D. Treatment failure on standard dose at baseline 12.3


E. Early molecular respondersd Not reached

F. Non-early molecular responders 11.0

Difference, subgroups E vs F p < 0.001

AEs

Haematological AEs above grade 2

Anaemia 71 12 16.9%a

Neutropenia 71 13 18.3%a

Thrombocytopenia 71 0 0%

Non-haematological AEs above grade 2

Grade 3 oedema 71 2 2.8%a

Other AEs above grade 2 71 0 0%

Other AEsg

Stopped imatinib owing to intolerable toxicity 71 0 0%

AP, accelerated phase; BC, blast crisis; CCyR, complete cytogenetic response; CP, chronic phase.a Calculated by reviewer.b Patients who were AP or BC failed to reach a CCyR during the study.c Stated that frequency of achieving a CCyR was higher for partial responders at baseline than for less than partial responders at baseline (data

not reported).d Early molecular responder defined as a molecular reduction of > 50% within 6 months.e Stated that early molecular-responder patients reached CCyR more frequently at 6 and 12 months (p = 0.010 and p < 0.001, respectively).f Unclear whether p-value applies to individual comparisons of CP vs AP and CP vs BC or a pooled comparison of CP vs AP + BC.g Stated narratively that nausea, vomiting, oedema, muscle cramps, fatigue and diarrhoea were common non-haematological toxicities, but data

not reported.



Quality appraisal

1. General


1.2. Were the case series collected at more than one centre? YES


1.4. Are patient characteristics adequately described? YES (limited to ethnicity, age, sex and CML characteristics)

1.5. How easy is it to assess generalisability of the results? HIGH (specifically a Korean population of known age range and CML status, although potential prognostic factors such as weight not reported)


2.1. Are inclusion and exclusion criteria clearly reported? YES

2.2. Were data collected prospectively? YES

2.3. Were patients recruited consecutively? NOT REPORTED (a date range for recruitment is given)


3.1. Did all the participants receive the same intervention? NO (subgroups received different dose escalations or reductions if warranted)

3.2. Is the use of any concurrent therapies adequately described? NO (not reported whether or not there were any concurrent therapies)


4.1. Was an ITT analysis performed? UNCLEAR (not explicitly reported; however, data for CyRs and molecular responses were conservatively presented as percentages of all patients rather than as percentages of those available and eligible for assessment)

4.2. Were dropouts from the study adequately described? YES

100 Appendix 4

Rajappa et al.8

Study details


Study: Rajappa et al. (2010)8

Design: Cohort single arm judged to be prospective, although unclear reporting

Chronic phase: Yes

AP: No

BC: No

Country: India

No. of centres: Assumed one (not reported; all authors from one centre)

Notes:

Study focuses on kinase domain mutations

Inclusion criteria

CP-CML resistant to imatinib 400 mg/day. No other details reported

Primary resistance defined as treatment failure to 400 mg/day of imatinib, i.e. failure to achieve CHR after 3 months, failure to achieve any CyR after 6 months, MCyR after 12 months, and CCyR after 18 months of therapy

Secondary resistance defined as loss of CCyR or rising WBC counts to > 10 × 109/l on two occasions more than 4 weeks apart, progression to AP or BC

Exclusion criteria

Patients with AP or BC

Arm 1

n: 90

Drug: HDI


Dose details

Dose escalated from 400 to 800 mg/day for all participants


None reported

Event-free survival

Defined as: ‘time from dose escalation to loss of CHR or CCyR, failure to achieve CHR at 3 months, progression to AP or BC, no CyR at 6 months, less than MCyR at 12 months and no CCR at 18 months or death from any cause’

Transformation-free survival

Defined as time from dose escalation until transformation to AP or BC, or death due to any cause

OS

Defined as time from dose escalation to death due to any cause

AEs

AP, accelerated phase; BC, blast crisis; CCyR, complete cytogenetic response; CP-CML, chronic-phase chronic myeloid leukaemia; HDI, high-dose imatinib; MCyR, major cytogenetic response; OS, overall survival; WBC, white blood cell.


Intervention

n k Mean, median or percentage

Demographics

Age, years: mean ± SD (range) 90 35.7 ± 12 (18 to 65)

Sex (n male) 90 64 71.1%

Imatinib failure

Intolerancea

Primary resistance 90 30

Secondary resistance 90 60

Disease groupb

Primary haematological resistance 90 10 11.1%

Primary cytogenetic resistance 90 20 22.2%

Loss of haematological response 90 55 61.1%

Loss of CyR 90 5 5.5%

Prior therapy (stated that participants received only imatinib 400 mg/day and HU; no other prior therapy)

Median (range) time (months) from diagnosis to start of imatinib 400 mg/day 90 5 (0.5 to 20)

< 6 months 75

> 6 months 15

Median (range) time (months) on imatinib 400 mg/day before resistance 90 18 (3 to 48)

≤ 18 months 65

> 18 months 25



Intervention

n k Mean, median or percentage

Best response to imatinib 400 mg/day

CCyR 90 10 11.1%

PCyR 90 21 23.3%c

Minor CyR 90 58 64.4%d

CHR 90 80 88.8%

MCyR to imatinib 400 mg/day 90 41 45.5% e

Laboratory and other clinical parameters

Median (range) haemoglobin concentration (g/dl) 90 11.2 (7.9 to 15.1)

Median (range) total leucocyte count (109/l) 90 11 (3.7 to 180)

Median (range)% blasts 90 2 (0 to 9)

Median (range)% basophils 90 4 (0 to 12)

Median (range)% platelets 90 2.7 (0.9 to 11.9)

Sokal score low and intermediate 90 60

Sokal score high 90 30

BCR–ABL mutations 90 29 32.2%

CCyR, complete cytogenetic response; CyR, cytogenetic response; HU, hydroxycarbamide; MCyR, major cytogenetic response; PCyR, partial cytogenetic response; SD, standard deviation.a Focus was on resistance (all participants); intolerance not reported.b At dose escalation.c Reported by the authors as 23.5%.d Reported by the authors as 65.4%.e Reported by the authors as 44.5%.

Results

Intervention

N kPercentage, median or p-value

At

Event-free survival at follow-up 90 35 39%

OS at follow-up 90 84 93%

Follow-up time unclear

CCyR

All participants 90 25 27.7%

Cytogenetic failure subgroup 26 13 50%

Haematological failure subgroup 64 12 18.75%


PCyR

All participants 90 10 11.1%a

Cytogenetic failure subgroup 26 6 23%

Haematological failure subgroup 64 4 6.25%


MCyR 90 35 39%

Median (range) time to CyR (months) 11 (6 to 18)

CHR 90 50 55.5%

102 Appendix 4

Intervention


Estimated 2-year outcomes

Event-free survival

All participants 90 34%

Cytogenetic failure subgroup 26 73%

Haematological failure subgroup 64 22%

Difference between subgroups p=0.0018

Event-free survival for patients achieving a MCyR to dose escalation


Cytogenetic failure subgroup 90%

Haematological failure subgroup 51%

Difference between subgroups p=0.0006

OS




Difference between subgroups Stated NS

Transformation-free survival





Events at median follow-up of 18 (range 3–40) months 90 55 61%

Failure to achieve CHR 55 37 67.3%b

Loss of haematological response 55 2 3.6%

Failure to achieve CyR 55 7 12.7%

Progression to AP or BC 55 3 5.5%b

Death 55 6 10.9%b

Consequences of haematological toxicity

Dose decrease 90 16 18%

Dose interruption 90 31 34%

Discontinuation due to AEs 90 3 3%

Able to continue imatinib dose > 600 mg/day 90 60 67%c



Intervention


AEs

Grades 3–4 haematological AEs

Anaemia 90 27 30%

Leucopenia 90 28 31%

Neutropenia 90 35 39%d

Thrombocytopenia 90 19 21%

Non-haematological AEs

Superficial oedema 90 55 61%

Musculoskeletal pain 90 35 39%

Fatigue 90 27 30%

Anorexia 90 26 or 23e 29% or 25.55%e

Rash 90 24 27%

Diarrhoea 90 24 27%

Dyspepsia 90 13 14%

Nausea/vomiting 90 10 11%

Mucositis/oral ulcers 90 9 10%

AP, accelerated phase; BC, blast crisis; CCyR, complete cytogenetic response; MCyR, major cytogenetic response; PCyR, partial cytogenetic response; NS, not statistically significant; OS, overall survival.a Reported by the authors as 11.3%.b Percentage reported by authors differed by ± 0.1.c Reported by the authors as 76%.d Reported incorrectly by the authors as 44%.e Two entries for anorexia are given by the authors in table VI, but unclear which is correct.

104 Appendix 4

Quality appraisal

1. General


1.2. Were the case series collected at more than one centre? NOT REPORTED (but all authors based at one centre)


1.4. Are patient characteristics adequately described? NO (this study appears to be on an Indian population but ethnicity and socioeconomic status are not reported)

1.5. How easy is it to assess generalisability of the results? LOW (appears to be single-centre study)


2.1. Are inclusion and exclusion criteria clearly reported? YES (although limited)

2.2. Were data collected prospectively? NOT REPORTED (cannot ascertain from description of methods)

2.3. Were patients recruited consecutively? YES (stated in methods)


3.1. Did all of the participants receive the same intervention? YES (but timing of intervention varied among patients and is not reported, hence giving a broad range of imprecise follow-up times)

3.2. Is the use of any concurrent therapies adequately described? NO (not reported whether there were any concurrent therapies)


4.1. Was an ITT analysis performed? UNCLEAR (not explicitly reported; stated that only patients with at least one cytogenetic evaluation after 6 months of dose escalation were analysed, but not whether or not all 90 participants analysed met this criterion; also, some percentages incorrect – unclear whether or not a different denominator used)

4.2. Were dropouts from the study described? NO

Note: this paper gives only a vague indication of follow-up time (median and wide range). This is a major limitation that is not captured by the quality-appraisal criteria above.

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